Clindamycin to reduce preterm birth in a low resource setting: a randomised placebo-controlled clinical trial.

OBJECTIVE: To determine whether oral clindamycin reduces the risk of preterm birth (PTB) in women with abnormal vaginal microflora as evidenced by a vaginal pH ≥5.0. DESIGN: Randomised double-blind placebo-controlled trial. SETTING: Rural southern India. POPULATION: Pregnant women with a singleton fetus between 13+0/7 weeks and 20+6/7 weeks. METHODS: Pregnant women were recruited during prenatal visits in Karnataka, India, from October 2013 to July 2015. Women were required to have a singleton fetus between 13+0/7 weeks and 20+6/7 weeks and an elevated vaginal pH (≥5.0) by colorimetric assessment. Participants were randomised to either oral clindamycin 300 mg twice daily for 5 days or an identical-appearing placebo. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PTB, defined as delivery before 37+0/7 weeks. RESULTS: Of the 6476 screened women, 1727 women were randomised (block randomised in groups of six; clindamycin n = 866, placebo n = 861). The demographic, reproductive, and anthropomorphometric characteristics of the study groups were similar. Compliance was high, with over 94% of capsules being taken. The rate of PTB before 37 weeks was comparable between the two groups [clindamycin 115/826 (13.9%) versus placebo 111/806 (13.8%), between-group difference 0.2% (95% CI -3.2 to 3.5%, P = 0.93)], as was PTB at less than 34 weeks [clindamycin 40/826 (4.8%) versus placebo group 37/806 (4.6%), between-group difference 0.3% (95% CI -1.8 to 2.3%, P = 0.81)]. No differences were detected in the incidence of birthweight of<2500 g, <1500 g, miscarriage, stillbirth or neonatal death. CONCLUSION: In this setting, oral clindamycin did not decrease PTB among women with vaginal pH ≥5.0. TWEETABLE ABSTRACT: Oral clindamycin between 13+0/7 and 20+6/7 weeks does not prevent preterm birth in women with a vaginal pH ≥5.0.

Global Network for Women's and Children's Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system.

OBJECTIVE: We sought to classify causes of stillbirth for six low-middle-income countries using a prospectively defined algorithm. DESIGN: Prospective, observational study. SETTING: Communities in India, Pakistan, Guatemala, Democratic Republic of Congo, Zambia and Kenya. POPULATION: Pregnant women residing in defined study regions. METHODS: Basic data regarding conditions present during pregnancy and delivery were collected. Using these data, a computer-based hierarchal algorithm assigned cause of stillbirth. Causes included birth trauma, congenital anomaly, infection, asphyxia, and preterm birth, based on existing cause of death classifications and included contributing maternal conditions. MAIN OUTCOME MEASURES: Primary cause of stillbirth. RESULTS: Of 109 911 women who were enrolled and delivered (99% of those screened in pregnancy), 2847 had a stillbirth (a rate of 27.2 per 1000 births). Asphyxia was the cause of 46.6% of the stillbirths, followed by infection (20.8%), congenital anomalies (8.4%) and prematurity (6.6%). Among those caused by asphyxia, 38% had prolonged or obstructed labour, 19% antepartum haemorrhage and 18% pre-eclampsia/eclampsia. About two-thirds (67.4%) of the stillbirths did not have signs of maceration. CONCLUSIONS: Our algorithm determined cause of stillbirth from basic data obtained from lay-health providers. The major cause of stillbirth was fetal asphyxia associated with prolonged or obstructed labour, pre-eclampsia and antepartum haemorrhage. In the African sites, infection also was an important contributor to stillbirth. Using this algorithm, we documented cause of stillbirth and its trends to inform public health programs, using consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system. TWEETABLE ABSTRACT: Major causes of stillbirth are asphyxia, pre-eclampsia and haemorrhage. Infections are important in Africa.

A prospective cause of death classification system for maternal deaths in low and middle-income countries: results from the Global Network Maternal Newborn Health Registry.

OBJECTIVE: To describe the causes of maternal death in a population-based cohort in six low- and middle-income countries using a standardised, hierarchical, algorithmic cause of death (COD) methodology. DESIGN: A population-based, prospective observational study. SETTING: Seven sites in six low- to middle-income countries including the Democratic Republic of the Congo (DRC), Guatemala, India (two sites), Kenya, Pakistan and Zambia. POPULATION: All deaths among pregnant women resident in the study sites from 2014 to December 2016. METHODS: For women who died, we used a standardised questionnaire to collect clinical data regarding maternal conditions present during pregnancy and delivery. These data were analysed using a computer-based algorithm to assign cause of maternal death based on the International Classification of Disease-Maternal Mortality system (trauma, termination of pregnancy-related, eclampsia, haemorrhage, pregnancy-related infection and medical conditions). We also compared the COD results to healthcare-provider-assigned maternal COD. MAIN OUTCOME MEASURES: Assigned causes of maternal mortality. RESULTS: Among 158 205 women, there were 221 maternal deaths. The most common algorithm-assigned maternal COD were obstetric haemorrhage (38.6%), pregnancy-related infection (26.4%) and pre-eclampsia/eclampsia (18.2%). Agreement between algorithm-assigned COD and COD assigned by healthcare providers ranged from 75% for haemorrhage to 25% for medical causes coincident to pregnancy. CONCLUSIONS: The major maternal COD in the Global Network sites were haemorrhage, pregnancy-related infection and pre-eclampsia/eclampsia. This system could allow public health programmes in low- and middle-income countries to generate transparent and comparable data for maternal COD across time or regions. TWEETABLE ABSTRACT: An algorithmic system for determining maternal cause of death in low-resource settings is described.

Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial.

OBJECTIVE: Sublingual misoprostol produces a rapid peak concentration, and is more effective than oral administration. We compared the postpartum measured blood loss with 400 µg powdered sublingual misoprostol and after standard care using 10 iu intramuscular (IM) oxytocin. DESIGN: Double-blind randomised controlled trial. SETTING: A teaching hospital: J N Medical College, Belgaum, India. SAMPLE: A cohort of 652 consenting eligible pregnant women admitted to the labour room. METHODS: Subjects were assigned to receive the study medications and placebos within 1 minute of clamping and cutting the cord by computer-generated randomisation. Chi-square and bootstrapped Student's t-tests were used to test categorical and continuous outcomes, respectively. MAIN OUTCOME MEASURES: Measured mean postpartum blood loss and haemorrhage (PPH, loss ≥ 500 ml), >10% pre- to post-partum decline in haemoglobin, and reported side effects. RESULTS: The mean blood loss with sublingual misoprostol was 192 ± 124 ml (n=321) and 366 ± 136 ml with oxytocin IM (n=331, P ≤ 0.001). The incidence of PPH was 3.1% with misoprostol and 9.1% with oxytocin (P=0.002). No woman lost ≥ 1000 ml of blood. We observed that 9.7% and 45.6% of women experienced a haemoglobin decline of >10% after receiving misoprostol and oxytocin, respectively (P ≤ 0.001). Side effects were significantly greater in the misoprostol group than in the oxytocin group. CONCLUSION: Unlike other studies, this trial found sublingual misoprostol more effective than intramuscular oxytocin in reducing PPH, with only transient side effects being greater in the misoprostol group. The sublingual mode and/or powdered formulation may increase the effectiveness of misoprostol, and render it superior to injectable oxytocin for the prevention of PPH. Further research is needed to confirm these results.

Consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of Karnataka, India.

OBJECTIVE: To determine whether consanguinity adversely influences pregnancy outcome in South India, where consanguinity is a common means of family property retention. STUDY DESIGN: Data were collected from a prospective cohort of 647 consenting women, consecutively registered for antenatal care between 14 and 18 weeks gestation, in Belgaum district, Karnataka in 2005. Three-generation pedigree charts were drawn for consanguineous participants. χ (2)-Test and Student's t-test were used to assess categorical and continuous data, respectively, using SPSS version 14. Multivariate logistic regression adjusted for confounding variables. RESULT: Overall, 24.1% of 601 women with singleton births and outcome data were consanguineous. Demographic characteristics between study groups were similar. Non-consanguineous couples had fewer stillbirths (2.6 vs 6.9% P=0.017; adjusted P=0.050), miscarriages (1.8 vs 4.1%, P=0.097; adjusted P=0.052) and lower incidence of birth weight <2500 g (21.8 vs 29.5%, P=0.071, adjusted P=0.044). Gestation <37 weeks was 6.2% in both the groups. Adjusted for consanguinity and other potential confounders, age <20 years was protective of stillbirth (P=0.01), pregnancy loss (P=0.023) and preterm birth (P=0.013), whereas smoking (P=0.015) and poverty (P=0.003) were associated with higher rates of low birth weight. CONCLUSION: Consanguinity significantly increases pregnancy loss and birth weight <2500 g.

Drape estimation vs. visual assessment for estimating postpartum hemorrhage.

OBJECTIVE: To compare (1) visual estimation of postpartum blood loss with estimation using a specifically designed blood collection drape and (2) the drape estimate with a measurement of blood loss by photospectrometry. METHODS: A randomized controlled study was performed with 123 women delivered at the District Hospital, Belgaum, India. The women were randomized to visual or drape estimation of blood loss. A subsample of 10 drape estimates was compared with photospectrometry results. RESULTS: The visual estimate of blood loss was 33% less than the drape estimate. The interclass correlation of the drape estimate to photospectrometry measurement was 0.92. CONCLUSION: Drape estimation of blood loss is more accurate than visual estimation and may have particular utility in the developing world. Prompt detection of postpartum hemorrhage may reduce maternal morbidity and mortality in low-resource settings.

Postpartum hemorrhage in resource-poor settings.

Despite the strong interest of international health agencies, worldwide maternal mortality has not declined substantially over the past 10 years. Postpartum hemorrhage (PPH) is the most common cause of maternal death across the world, responsible for more than 25% of deaths annually. Although effective tools for prevention and treatment of PPH are available, most are not feasible or practical for use in the developing world where many births still occur at home with untrained birth attendants. Application of many available clinical solutions in rural areas would necessitate substantial changes in government infrastructure and in local culture and customs surrounding pregnancy and childbirth. Before treatment can be administered, prompt and accurate diagnosis must be made, which requires training and appropriate blood measurement tools. After diagnosis, appropriate interventions that can be applied in remote settings are needed. Many uterotonics known to be effective in reducing PPH in tertiary care settings may not be useful in community settings because they require refrigeration and/or skilled administration. Moreover, rapid transfer to a higher level of care must be available, a challenge in many settings because of distance and lack of transportation. In light of these barriers, low-technological replacements for treatments commonly applied in the developed-world must be utilized. Community education, improvements to emergency care systems, training for birth attendants, misoprostol, and Uniject have shown promise as potential solutions. In the short term, it is expedient to capitalize on practical opportunities that utilize the existing strengths and resources in each community or region in order to implement appropriate solutions to save the lives of women during childbirth.

Conducting international collaborative research in developing nations.

International research partnerships bring together some of the best and the brightest in an effort to tackle global health problems. Such collaborations also pose complex challenges, such as maintaining ethical principles in the conduct of research in developing nations. In implementing a randomized clinical trial to reduce postpartum hemorrhage (PPH) during childbirth in rural India, U.S. and Indian collaborators addressed three such issues: the appropriateness of an ethical randomized controlled trial in the developing world, the inclusion of a placebo arm, and the relevance of informed consent in a semiliterate rural population.

Evaluating contraceptive choice through the method-mix approach. An Indian Council of Medical Research (ICMR) task force study.

The method-mix approach was used to evaluate informed contraceptive choices in the present study. A total of 8,077 potential clients were given a balanced presentation of all available contraceptive methods in the national program, ie, the CuT 200 intrauterine device (IUD), low-dose combined oral pills (OC), condom, and sterilization (female/male) along with a new method, Norplant(R).(1) The majority of women opted for spacing methods; among them, the IUD was preferred by about 60% of clients, followed by condoms (9%), OC (6%), and Norplant (5%). Sterilization, mainly female, was accepted by about 17% of the women making an informed choice. The economic status of couples did not influence the contraceptive choices, as all the methods were offered free of cost in the present study, which is the current practice in the national program. Illiterate women more often accepted sterilization (about 25%) than did literate women (15%). This is because illiterate women had more children; about 30% of illiterate women had three or more children, as opposed to 16.2% of literate women. However, literacy status did not influence the choice of any specific spacing method. The study also revealed that, by encouraging potential clients to make an informed choice, they could override the provider's bias while accepting a particular type of spacing method. This is evident from the observation that Norplant was the first choice of the provider for 35% of the women, whereas only 5% of women preferred and accepted Norplant. The present study stresses an urgent need to promote the practice of informed choices in the national program with a variety of contraceptive options-especially, spacing methods for improving contraceptive prevalence and reproductive health in the country.

Return of fertility following discontinuation of Norplant-II subdermal implants. ICMR Task Force on Hormonal Contraception.

A total of 627 women who had discontinued the use of the Norplant-II implants for various reasons and were exposed to the risk of pregnancy were followed-up for two years for return of fertility. The cumulative conception rates in women who had discontinued due to planning pregnancy were 80.3 per 100 women at one year and 88.3 per 100 women at two years. The majority of women who did conceive (90 percent), had full-term normal live births; about 4 percent of women had spontaneous abortions, the remaining 6 percent decided on elective termination of pregnancy (ETP). The cumulative conception rates in women who discontinued due to bleeding irregularities and 'other reasons' were 64.5 and 55.8 per 100 women at one year and 77.9 and 75.1 per 100 women at two years, respectively. These rates were significantly lower as compared to those observed in women who discontinued due to planning pregnancy. A large proportion, about 40 percent, of women who conceived after discontinuation of the method due to bleeding irregularities and "other reasons," opted for ETP indicating that many women in these two groups did not desire another child and that such women need to be counselled for adopting another method of contraception. The spontaneous abortion rates observed in ex-users of Norplant-II implants (1.7 to 4.4% pregnancies) were comparable to the spontaneous abortion rates prior to Norplant-II implant use (3.6% pregnancies) indicating that ex-users of Norplant-II implants were not at a higher risk of spontaneous abortion.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Researchers at 15 Human Reproduction Centres of the Indian Council of Medical Research followed 627 women aged 18-35 who stopped using the subdermal Norplant-II system for different reasons, and thus were exposed to the risk of pregnancy, for 2 years to determine return of fertility. 20% conceived within 1 month of Norplant-II implant removal. The 6-month, 1-year, and 2-year pregnancy rates were 63.4%, 80.3%, and 88.3%, respectively. Neither duration of Norplant-II implant use nor bleeding patterns had an adverse effect on return of fertility. The 1-year and 2-year cumulative pregnancy rates for women who stopped due to bleeding irregularities and other reasons were lower than those who stopped due to planning a pregnancy. Return of fertility was delayed in women whose implants were removed after age 30 compared to those younger than 30 (1-year pregnancy rate, 66.3% vs. 83%; median time to conception, 6 vs. 3.8 months; p 0.05). The difference was not significant at 2 years, however. 89.7% of women who wanted pregnancy and became pregnant after discontinuation delivered full-term live infants. 4.4% had a spontaneous abortion. Women who discontinued the implant system to conceive were less likely to opt for an induced abortion than those who discontinued for irregular bleeding and other reasons (5.9% vs. 36.4-41.6%), suggesting that many women did not want another child and need to be counseled about adopting and offered another contraceptive method. The spontaneous abortion rates for women who discontinued for irregular bleeding and other reasons were 1.7% and 2.7%. No group of former Norplant II users suffered a spontaneous abortion rate greater than the pre-Norplant II use rate (3.6%). These findings show that the Norplant-II implant system does not delay return to fertility in women who stop using it to become pregnant.

Foetal growth parameters--clinical versus ultrasonographic.

The study was conducted in 2831 pregnant women with no diagnosed complication at the time of registration to obtain normal foetal growth pattern for clinical and ultrasonographic parameters. Normal values for maternal weight, fundal height and abdominal girth for clinical and biparietal diameter, abdominal circumferences and femoral length for ultrasonographic parameters are presented. Clinical and ultrasonographic parameters were compared for their efficacy in prediction of low birth weight. Neither clinical nor ultrasonographic parameters were found to be satisfactory in identifying the foetus at risk of low birth weight. It has been found that clinical parameters for routine monitoring are as effective as ultrasonographic parameters and have the added advantage of being easily replicable at the peripheral level of health care.

Phase III-clinical trial with Norplant-2 (covered rods). Report of a 24-month study. National Programme of Research in Human Reproduction. Division of Human Resource Development Research Indian Council of Medical Research Ansari Nagar, New Delhi, India.

In a phase III multicentre clinical trial, the subdermal implant NorplantR-2 was studied for its clinical use effectiveness, safety and bleeding pattern. A total of 1466 healthy volunteers, with no contraindication to steroid use, were observed for 29,669 woman-months of use. One method failure was reported at 18 months of NorplantR-2 use. The method was associated with altered menstrual pattern with a trend towards reduced blood loss. The continuation rates were 88.1 and 73.5 per 100 users at 12 and 24 months of use, respectively. Menstrual disturbance, mainly prolonged bleeding, accounted for the majority of the discontinuations. Removal of NorplantR-2 due to local infection was rare (0.4 per 100 users at 24 months). In similar clinical trial conditions, the continuation rate with NorplantR-2 is significantly higher than those observed with LNG IUD and injectable contraceptives, norethisterone oenanthate 200 mg given every 60 +/- 5 days, and is comparable to that of CuT 200 IUD.